DE2244571A1 - TRIAZOLO-BENZODIAZEPINE AND THE METHOD OF MANUFACTURING IT - Google Patents

Description

LAWYERS

DR. JUR. DIPL-CHEM. WALTEi BiE ALFRED HOEPPENER

OR. JUR. DiPL-CHEM. H.-J. WOW DR. JUR. HANS CHR. AX

623 FRANKFURT AM

ADftOHSIBAS6i SS

"MAXIMUM!

244571 »ep. wi

Our No. 18 0-6

The Upjohn Company Kalamazoo _s Micho ₉ VoSt..A,

Triasolo-benz odiazepines and process for their preparation

The present invention relates to novel _s-t 6 disufostituierte 4H ~ s-Tria2; OLQ £ * { "3-a3 £ lj ^ £ 3foen Qdiasepine of formula

309812/1249

ORIGINAL INSPECTED

wherein R _{1 is} hydrogen or a lower alkyl radical with 1 "to 3 carbon atoms, R _{2 is} a pyridyl, 2-pyrimidyl, puryl, pyrryl or thienyl radical, a lower alkyl radical with 1 to 3 carbon atoms, lower alkenyl radical with 2 to carbon atoms, Cycloalkyl radical with 5 to 7 carbon atoms or cycloalkenyl radical with 5 to 7 carbon atoms, and R, and R. Hydrogen atoms, halogen atoms, nitro or trifluoromethyl groups, lower alkoxy radicals with 1 to 3 carbon atoms, lower alkyl mercapto groups with 1 to 3 carbon atoms or lower dialky! Amino groups with lower ones Alkyl radicals with 1 to 3 carbon atoms

dj_g

place. The invention also relates to pharmacology compatible acid addition salts of these compounds and a process for their preparation. The new connections formula II are useful as sedatives, hypnotics, Anticonvulsants, tranquilizers, and muscle relaxers in mammals and birds, they are also useful as additives to feed for livestock and poultry.

The substituent in the 1-position is exclusively one Trifluoromethyl group, the substituent in 6-3 position can be Pyridyl, 2-pyrimidyl, furyl, pyrryl or thienyl radical, a lower alkyl radical with 1 to 3 carbon atoms, lower alkenyl radical with 2 to 3 carbon atoms, cycloalkyl radical with 5 to 7 carbon atoms or cycloalkenyl radical with 5 to 7 carbon atoms.

The new compounds according to the invention and the process for their preparation are represented by the following formula reproduced:

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H-NH ₂

CF ₃ COOK + _R

Il

In the oxy formulas, R. denotes a hydrogen atom or a lower alkyl radical with 1 to 3 carbon atoms, R ₂ denotes a pyridyl, 2-pyrimidyl, furyl, pyrryl or thienyl radical, and a lower alkyl radical with 1 Ms 3 carbon atoms,

309812/1249

lower alkenyl radical with 2 to 3 carbon atoms, cycloalkyl radical with 5 to 7 carbon atoms or a cycloalkenyl radical with 5 to 7 carbon atoms, and R, and R. represent hydrogen atoms, halogen atoms, nitro or trifluoromethyl groups, lower alkoxy groups with 1 to 3 carbon atoms, lower alkyl mercapto groups with 1 to 3 carbon atoms or lower dialky amino groups with lower alkyl groups with 1 to 3 carbon atoms.

Examples of lower alkyl groups are methyl, ethyl, propyl and isopropyl, examples of lower alkenyl groups with 2 to 3 carbon atoms include the vinyl, 1-propenyl and isoprcpenyl radical. Examples of cycloalkyl radicals with 5 to 7 carbon atoms include cyclopentyl, cyclohexyl and cycloheptyl groups, and examples of cycloalkenyl groups with 5 to 7 carbon atoms include the 1-cyclopentenyl, 1-Cyclohexenyl and 1-Cycloheptenyl radical. As examples fluorine, chlorine, bromine and iodine are mentioned for halogen, examples of lower alkoxy radicals with 1 to 3 carbon atoms are methoxy, ethoxy, propoxy and isopropoxy. Examples of alkyl mercapto groups having 1 to 3 carbon atoms include the methylthio, ethylthio, propylthio and isopropylthio radical, and as examples of dialkyl lower amino groups with alkyl radicals having 1 to 3 carbon atoms be the dimethylamine, diethylamino, methylethylamino, methylpropylamino, ethylpropylamino, dipropylamino, Diisopropylamino, methylisopropylamino and ethylisopropylamino radicals called.

The new compounds of formula II also include the pharmacologically acceptable acid addition salts, e.g. the hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, Cyclohexanesulfamate, methanesulfonates and the like. By reacting a compound of formula II with a

309812/1249

Excess of the pharmacologically acceptable in question Acid can be obtained.

The compounds of formula II can be used in the form of the free base or in the form of their acid addition salts as sedatives _f hypnotics, antispasmodics ₉ tranquilizers and muscle relaxers in mammals and birds, ■ also as feed additives to accelerate the growth rate and increase feed utilization "The free bases and Acid addition salts of the compounds of the formula II can be used in the same way as the known muscle relaxants, for example diazepam or mephenesin, for the treatment of mammals and YögelK, taking into account the activity of the compounds II in the dosage,

According to the invention, pharmaceutical preparations for oral, parenteral and rectal use are envisaged, e.g. tablets, powder packets, sachets, dragees, capsules, solutions, .Suspensions ^ sterile injectable forms, suppositories and the like. Suitable diluents such as carbohydrates (lactose), proteins, lipids, Galciuaphosphat, corn starch, are stearic acid, methyl cellulose and used like ₀ * to prepare solutions or suspensions can be oils such as coconut oil, sesame oil, safflower oil, Baumv / ollsamenöl ₉ peanut oil and the like, "use" Furthermore, sweeteners _s dyes and Flavors are added »

For mammals and birds, feed premixes with starch, oatmeal, dried fish meat clip Fisehmehl _P cereal "flour or the like" can be prepared , 1 to 2o mg / feg

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22U571

used in oral or injectable preparations. The compounds can be used to relieve muscle spasms To facilitate domestic and farm animals, for example can arise after strenuous work, also for the elimination of tension and anxiety in mammals or birds, as these can occur during shipping. The compounds of the formula II and their pharmacologically acceptable acid addition salts used in doses of 0.03 to 50 mg / animal / day to increase growth, putter intake and feed conversion, Increase milk and egg production

The starting compounds of the formula I are obtained according to the procedure of Example 1. The ones used there Starting materials for their part are prepared according to the instructions for preparations 1 and 2.

The method according to the invention is characterized in that that one is a 5-substituted 3H-1,4-benzodiazepin-2-ylhydrazine (I) at low temperature (about -5 to about -1o ° C) to trlfluoroacetic acid and then the resulting Reaction mix to about 60-1oo ° C for about 1 to 5 hours heated, the corresponding 6-substituted 1-trifluoromethyl.4H-s-triazolo / "4» 3-a7 / "i, ^ Tbenzodiazepine (II) receives. The compound of formula II is worked up in a conventional manner, e.g., by extraction, preferably after neutralization of the reaction mixture. The purification is carried out by chromatography, crystallization and Recrystallize.

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Preparation 1

7 ~ Brora-1 _f 3-dihydro-5- (2-pyridyl) -2H-1,4 ~ benzQdiasepin-2-th.ion.

A solution of 6.55 g of 7-bromo-1 p3 ~ dihydro-5 »* (2- ° pyridyl) -2H ~ 1,4-"benz; odiazepiii-2-one (preparation see "Pharm _e Sci . ^> 3 _t 264) in 4oo ml of dry pyridine is heated under stirring in a nitrogen atmosphere in an oil bath with 5s, o5 g of phosphorus pentasulfide to about 11o-12o ° C for about * 1 hour, then cooled and concentrated in vacuo * In the residue Any remaining pyridine is removed by adding xylene and toluene, concentrating in vacuo and repeating this process. The dark brown, solid residue is mixed with a mixture of aqueous sodium carbonate solution and chloroform

triturated and the resulting, finely divided, brown solid is filtered off, washed with water, dissolved in a mixture of chloroform and ethanol and decolorized with activated charcoal. Crystallization product obtained is 3, 39 g! A melting point of 249 ° C (decomposition) and o, 559 g of melting point 243 ⁰ C (decomposition). The analysis sample is crystallized from ethanol, which gives 7-bromo-1,3-diliydro-5- (2-pyridyl) -2H-1 _l 4-benzodiazepine-2 »thione from P. 245-246 ° C ( Decomposition), UV spectrum (ethanol) final absorption Xmax 219 m / u (G = 21 o5o), λ-max 3o2 m / u (G = 24 100). Anal. Ber. for 0..H ₁₀ BrN ₅ S:

C: 50.61; H: 3.03; Br; 24, o6j N; 12.65; S: 9.65; Found: C: 49.98; H: 2.73; Bri 24.31? N: 12 _s 6o; S; 9.59.

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Preparation 2

7-chloro-1,3-dihydro-5-methyl-2II-1 ^ -benzodiazepine - ^ - tiiion.

To a hot solution of 1 g (5 millimoles) of 7-chloro-1,3-dihydro-5-methyl-2H-1,4-benzodiazepin-2-one (for preparation see PR-PS 1,391,752) in 150 ml 1.1 g (5 millimoles) of phosphorus pentasulfide are added to xylene. The mixture is refluxed in a nitrogen atmosphere for about 4 hours, then cooled and filtered, the filtrate containing only a little material. The pesticide filtered off is treated with hot water and filtered again. The filtrate is adjusted to pH 6-8 with 2oj6% sodium hydroxide solution, the white pesticide is then extracted with ethyl acetate, whereby 129 mg of the crude product are obtained. The pesticide initially obtained is again mixed with water treated, the aqueous phase is made basic with sodium bicarbonate and then extracted with hot ethyl acetate, thereby obtaining 1 g of a brown pesticide. This material plus the above 129 mg of boiled product are on 130 g of silica gel using 50? S ethyl acetate / 50 # cyclohexane The product obtained from the column is recrystallized from ethyl acetate, giving 455 mg of product with a melting point of 2o5-2o6 ° C. (decomposition) A previously prepared sample of the product 7-chloro-1,3-dihydro-5 -methyl-2H-1,4-benzodiazepine-2-thione melted at 2o1-2o3 ° C. Anal. calc. for C ₁₀ H ₉₂

C: 53.45; H: 4.04; N: 12.47; Cl: 15.78; 3: 14.27; Found: C: 53.29; H: 3.87; N: 12.16; Cl: 15.88; S: 14.67.

If the procedure of preparations 1 and 2 is repeated, but using other known 2H-1,4-benzodiazepin-2-ones such as e.g.

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(1) 7-Bromo-1,3-dihydro-5-ethy-yl-2H-1,4-'ben2sodiazepin-2 ~ one _>

(2) 9-chloro-1,3-dihydro-3-inetyiyl * -5-propyl-2H-1 ^ -bengcKtiazepiii 2 ~ on, '

(3) 1,3 ~ dihydro-5- (4-pyridyl) -9-trifluoromethyl-2H-1,4-benzodiazepin ~ 2 ~ one,

(4) 7-I> iii.tliylamino-1,3-dihydro-9-ethoxy-3-met] iyl-5- (3-pyridyl) 2H-1,4 ~ T3enzodiazepin-2-one,

(5) 1,3-Dihydro-7-ätliox: y-5 ~ (2-pyrryl _# _ _> -2H-1,4- ^- faenzodiazepin'-2-one,

(6) 1,3 ~ Hihydro-8-ätliylthio-9-nitro-5- (2-. Pyrimidyl) -Si 1,4- ■ benzodiazepin-2-one,

(7) 7-Ciilor-1 _t 3-di] aydro-5- (2-pyridyl) -2H-1 ^ - "benzodiazepin« 2-one,

(8) 1,3-Dihydro-3-ethyl-7-fluoro-5- (2 ~ furyl) -9-raethyItMo-2H-1,4- "benzodiazepin-2-one,

(9) 1,3-Diliydr.o-7 * "ätliyl-5- (3" i-uryl) -8-propoxy-2H-1,4-benzodiazepin-2-one,

(10) 7-Bromo-1,3-dihydro-9-dimethylamino-5- (2-pyrryl) -2H-1 _t 4-benzodiazepin-2-one, (11) 1,3-dihydro-8- nitro-5- (2-thienyl) -9-trifluoromethyl-2K-. 1 _l 4-benzodiazepin-2-one,

(12) 7-chloro-1,3-dihydro-5- (1-propenyi) -3-propyl-2H-1,4- ■ benzodiazepin-2-one,

(13) 1,3-Mhydro-5-isopropenyl-7-methoxy-2H-1,4- "benzodiazepin-2-one,

(14) 7-bromo-1,3-dihydro-5-vinyl-2H-1 _t 4- "benzodiazepin-2-one,

(15) 5-Cyclopeiityl-7-diethylaraino-1,3-dihydro-9-fluoro-2H-1,4- "benzodiazepin-2-one,

(16) 5-Cyclohexyl-i, 3 ~ dihydro * 3-ethyl-7-methoxy-2Ii-1,4 * benzodiazepine-S-on,

(17) 5-Cycloheptyl-i ^ -dihydro ^ -ethoxy ^ -propyl- ^ H-i, 4-benzodiazepin-2-one,

(18) 7-Broni-1,3-dihydro-5- (1-cyclopentenyl) -8-propoxy-2H-1 ^ -benzodiazepine - ^ - on,

30981

(19) 8-chloro-1,3-dihydro-5- (1-cyclohexenyl) -7-diethylainino-3-methyl-2H-1 _f 4-l3enzodiazepin-2-one,

(20) 1 _f 3-I) ihydro-5- (1-cycloheptenyl) -7-ethylthio-8-fluoro-3-propyl-2H-1,4- "benzodiazepin-2-one and the like, bo is obtained

(1) 7-Bromo-1,3-dihydro-5-ethyl-2H-1 ^ -

(2) 9-chloro-1,3-dihydro-3-methyl-5-propyl-2H-1 _f 4-benzodiazepine-2-thione,

(3) 1,3-dihydro-5- (4-pyridyl) -9-trifluoromethyl-2H-1 _t 4-bensodiazepine-2-thione,

(4) 7-Diethylamino-1,3-dihydro-9-ethoxy-3-methyl ~ 5- (3-pyridyl) 2H-1 _t 4- "benzodiazepine-2-thione,

(5) 1,3-dihydro-7-ethoxy-5- (2-pyrryl) -2H-1,4-benzodiazepine-2-thione,

(6) 1 _t 3-D ± hydro-8-ethylthio-9-nitro-5- (2-pyrimidyl) -2H-1,4-benzodiazepine-2-thione,

(7) 7-chloro-1,3-dihydro-5- (2-pyridyl) -2H-1 _t 4- "benzodiazepine ~ 2-thione,

(8) 1,3-Mhydro-3-ethyl-7-fluoro-5- (2-furyl) -9-methylthio-2H-1 ^ - "benzodiazepine - ^ - thione,

(9) 1 _t 3-I) ihydro-7-ethyl-5- (3-furyl) -8-propoxy-2H-1 _f 4- ■ benzodiazepine-2-thione,

(10) 7-bromo-1 _t 3-dihydro-9-dimethylamino-5- (2-pyrryl) -2H-1,4-benzodiazepine-2-thione,

(11) 1,3-Mhydro-8-nitro-5- (2-thienyl) -9-trifluoromethyl) -2H-1,4- "benzodiazepine-2-thione,

(12) 7-chloro-1,3-dihydro-5- (1-propenyl) -3-propyl-2H-1,4-benzodiazepine-2-thione,

(13) 1 ^ -Dihydro-S-isopropenyl - ^ - methoxy- ^ H-i, 4- "benzodiazepine-2-thione,

(14) 7-bromo-1,3-dihydro-5-vinyl-2H-1,4- "benzodiazepine-2-thione,

(15) 5-Cyclopenΐyl-7-diethylamino-1 _> 3-dihydΓo-9-fluoro-2H -. ^. 1,4- "benzodiazepine-2-thione,

(16) 5-Cyclohexyl-1 _l 3-dihydro-3-ai: hyl-7-methoxy-2II-1,4-benzodiazepine-2-thione,

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(17) 5-Cycloheptyl-i, 3-dihydro-7-ethoxy-3-propyl-2H-1, 4-benzodiazepine ~ 2-thione,

(18) 7-Bromo-1,3-dihydro-5- (1 -cyclopentenyl) '- 8-propoxy-2H-1,4-benEOdi izepin-2-thione _f

(19) 8-chloro-1,3-dihydro-5- (1-cyelohexenyl) -7-diethylamino. 3-methyl-2II-1,4-benzodiazepine-2-tliion,

(20) 1 _t 3-dihydro-5- (i-cycloheptenyl) -7-ethy-ylthio-8-fluoro-3-propyl-2H-1,4-benzodiazepine-2 "-thione and the like.

example 1

7-Bromo-5- (2-pyridyl) -3H-1,4-benzodiazepin ~ 2 ~ yl-hydrazine (i).

A mixture of 50 g of 7-bromo-1,3-dihydro-5- (2-pyridyl) -2H-1,4- "benzodia! 3epin-2-tliion (see preparation 1) and 17oo ml of methanol is treated with stirring with 50 g of hydrazine hydrate and then "stand at room temperature for about 1 hour 45 minutes calmly. During this time there will be a slow stream of nitrogen passed through the mixture. The resulting solution is concentrated in vacuo at 25-3o ° C, the residue is mixed with water and extracted with chloroform / The extract is dried over anhydrous potassium carbonate and concentrated under reduced pressure on a rotary evaporator replacing the chloroform with ethyl acetate. The resulting The mixture is crystallized, giving 26.6 g of 7-bromo-5- (2-pyridyl) -3H-1,4-benzodiazepin-2-ylhydrazine (I).

The procedure of Example 1 is repeated, but below Use of other 1,3-dihydro-2H-1,4-benzodiazepine-2-thiones such as.

309812/1249.

(1) 7-chloro ~ 1,3-dihydro-5-ethyl-2H-1,4-benzodiar.epin-2-thione,

(2) 9-Brora-1, 3-dihydro-3,5-diyn.ethyl-2H-1,4- "benzof] .as5epin-2-tiiJ or

(3) 1,3-Dihydro-5 - (^ i-pyridyl) -8 »tr if! Norme thyl-2U-1,4-benzodiazepine-2-thione,

(4) 7fS-DiUthoxy-1,3-dihydro-8-dimethylaraino-3-ethyl-5- (3-pyridyl) -2H-1,4-bensodiazepin-2-thione,

(5) 1,3-dihydro-7-methoxy-5- (2-pyrryl) -2H-1 _t 4-benzodia.sepin-2-thione,

(6) 1,3-dihydro-8-propylthio-9-nitro-5- (2-pyrimidyl) -2H «-1,4- ■ benzodiazepiii-2-thione,

(7) 7-chloro-1,3-dihydro-3-ethyl-8-fluoro-5- (2-furyl) -9-propylthio-2H-1 _t 4- "benzodiazepine-2-thione,

(8) 1,3-dihydro-8-ethyl-5- (3-i'xn- ⁱ yl) -9-methoxy-2H-1,4-benisodiazepine-2-thione,

(9) 7-chloro-1,3-dihydro-9-diethylamino-5- (2-pyrryl) -2H-1,4-benzodiazepine-2-thione _f

(10) 1,3-Dihydro-9-nitro-5- (2-thienyl) »8" trifluorraeth2 ^T l-2H-1 ^ -benzodiazepine - ^ - thione,

(11) 7-bromo-1,3-dihydro-5- (1-propenyl) -3-propyl-2H-1,4-benzodiazepine-2-thione,

(12) 1,3- ^ ihydro-5-isopropenyl-7-methoxy-2H-1,4-benzodiazepine-2-thione, . . ■

(13) 7-chloro-1,3-dihydro-8-ethoxy-5-vinyl ~ 2H ~ 1 ^ - "benzodiazepine-2-thione,

(14) 5-Cyclopentyl-7-diethylamino-1 _f 3-dihydro-2H-1,4-benzodiazepine-2-thione,

(15) 5-Cycloheptyl-1 ^ -dihydro - ^ - methoxy - ^ - methyl ^ H-i, 4-benzodiazepine-2-thione,

(16) 7-chloro-1,3-dihydro-5- (1-cyclopentyl) -8-ethoxy-2H-1,4-benzodiazepine-2-thione,

(17) 1,3-Dihydr0-5- (1-cycloheptenyl) -3,8-dimethy1-7-methylthio-2H-1,4-benzodiazepine-2-thione and the like, one obtains

ürvu

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7-chloro-5-ethyl-3H-1,4-benzodiazepin-2-yl-hydrazine _f

(2) 9 ~ bromo-3,5-dimethyl-3H-1,4-benzodiazepin ~ 2-yl-liydraEi: n,

(3) 5- (4-pyridyl) -8-trifluoromethyl-3H-1, ^ - benzodiazepineyl ~ liydrazine,

(4) 7, S-diethoxy-S-dimethylaininO'-J-ethyl-S-CJ-pyridylJ-oH-1,4-'benί5odiazepin-2-yl-hydra2in,

(5) 7 ~ methoxy ~ 5- (2-pyrryl) -5H-1,4-'benzodiazepin-2-yl-hydraain _ί

(6) 8-Propylthio-9-ni-tro-5- (2-pyriinidyl) ~ 3H-1,4- ^ eUZOaIaZePIn-2-yl-liydrazine,

(7) 7-chloro-3-ethyl-8-fluoro-5- (2-furyl) -9-propyItMο-3H-1,4 "■ 'benzodiazepin-2-yl-llydrazine,

(8) 8-Ethyl-5- (3- ± uryl) -9-metlioxy-3H-1,4-benzodiazepin-2-ylhydrazine,

(9) 7-chloro-9-diethylamino-5- (2-pyrryl) -3H-1,4- "benzodiazepin-2-yl-h.ydraiJin, .

(10) 9-nitro-5- (2-tliienyl) -8-trifluoromethyl-3H-1,4-'benaodiazepin-2-ylhydrazine,

(11) 7-bromo-5- (1-propenyl) -3-propyl-3H-1,4- "benzodiazei) iii-2-yl-hydrazine,

(12) 5-isopropenyl-7-niethoxy-3H-1,4- "benzodiazepiii-2-ylhydrazine,

(13) 7-chloro-8-ethoxy-5-vinyl-3H-1,4-benzodiazepin-2-ylhydrazine,

(14) 5-Cyclopentyl-7-diethylamino-3H-1,4-benzodiazepin-2-ylhydrazine,

(15) 5-Cycloheptyl-7-methoxy-3-nletlyl-3H-1,4-benzodiazepine- ^ 2-yl hydrazine,

(16) 7-chloro-5- (1-cyclopentenyl) -8-ethoxy-3H-1,4-benzodiazepin-2-ylhydrazine,

(17) 5- (1-Cycloheptenyl) -3,8-diniethyl-7-ynethylthio-3H -1,4-ben54odiazepin-2-yl-hydraziri and the like

:) ο 9 ar; /1 ? 4 a

Example 2

8-Bromo-6- (2-pyridyl) -1-trifluoromethyl-4H-s-triasolo / ~ 4,3 * & 7- _t 4j7benzodiazepine (II).

In an ice bath, 12 g of trifluoroacetic acid ground with 3 g 7-bromo-5- (2-pyridyl) -3H-1,4-ben2odiazepin ~ 2-yl-hydrazine (l) (For preparation see Example 1) mixed. The ice bath is then removed and the reaction mixture is poured out Steam bath heated for 2 hours. After cooling, sodium bicarbonate is added until the mixture is so thick that it does not

./ can be stirred with more. Then "little Yfasser and methylene chloride, then sodium carbonate is added until no further reaction occurs. The mixture It is then extracted with methylene chloride, the extract is dried over anhydrous potassium carbonate and concentrated. The residue is on 2oo g of oil gel using Chromatographed 1? £ methanol / 99 ^ chloroform. The the Product-containing fractions are combined and crystallized from ethyl acetate / Skellysolve B, whereby the 8-Bromo-6- (2-pyridyl) -1-trifluoromethyl-4H-s-triazolo / "~ 4,3-a7- / ~" 1,4,7benzodiazepine (II) receives.

If the compound obtained in this way is treated with a pharinakologically compatible oic acid, the corresponding one is obtained; £> aLz. Suitable acids for this purpose are e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, Lactic acid, citric acid, tartaric acid, methane sulfone » acid, toluenesulfonic acid, cyclohexanesulfamic acid, cyclohexanecarboxylic acid and d £; l. The reaction is carried out under conventional conditions in a solvent such as Ether, dioxane, tetrahydrofuran and the like.

Π Π I Il 1 2 4 ^r i BAD ORIGINAL

If the procedure of Example 2 is repeated, however, below Use of other raw materials I such as

iyl-2H-1,4 ~ "benzodiazepin-2-yl ~ hydrazine,

(2) 8-13rom-3,5-dimethyl-3H-1,4-benzodiazepin-2-yl-hyd.razine,

(3) 5- (4-pyridyl) -8-trifluoromethyl-3H-1,4-henzodiaiiopin ~ 2-yl - hydrazine,. -

(A) 7,9-Dietlioxy-8-dimethylamino-3-iflethyl-5 ~ (5-pyridyl) -3H ~. 1,4- * benzodiazepin-2-yl-hydrazine _>

(5) 7 ~ £ thoxy-5- (2-pyrryl) -3H-1,4- "benzodiazepin-2-yl ~ hydrazine, (6) 8-Propylthio-9-nitro-5- (2-pyrinddyl) -3H-1,4-benaodiazepJ.n-

(7) 7-chloro-3-ethyl-8-fluoro "5- (2-furyl) -9-propyl-thio-3H-1,4-benzodiazepin-2-yl-hydrasin,

(8) 8-ethyl-5- (3-furyl) -9-methoxy-3H-1,4- "benzodiazepin-2-yl-hydrasin,

(9) 7-chloro-9-diethylamino-5- (2-pyrryl) ~ 3H-1 _f 4- "benzodiazepin-2-yl-hydrazine,

(10) 9-Hitro-5- (2-thienyl) -8-trifluoromethyl-3H-1,4-'benzodiazepine. 2-yl hydrazine,

(11) 7-Bromo-5- (1-propenyl) -3-propyl ~ 3H-1, ^ - benzodiazepine-ayl-hydrazine,

(12) 5-I & opropenyl-7-methoxy-8-nitro-3H-1,4-benzodia2epin-2-yl-hydrazine,

(13) 7-Chloro-8-ethoxy-5-vinyl-3H-1,4- "benzodiazepin-2-ylhydrazine ^

(14) 5-Cyclopentyl ~ 7-dipropylamino-3H-1,4- "benzodiazepin-2 ~ yl" hydrazine,

(15) 5-Cycloheptyl-7-methoxy-3-propyl-3H-1,4- "benzodiazepin-2-yl-hydrazine,

(16) 7-chloro-5- (i-cyclopentenyl) -8-ethoxy-3H-1,4-t »enzodiazepin-2-yl-hydrazine,

(i7) 5- (i-Cycloheptenyl) -3,8-dimethyl-7-methylthio-3H-1,4-benzodiazepin-2- ylhydrazine, or the like, is obtained

309: 812/1249

(1) 8-chloro-6-methyl-1-trifluoromethyl-4H-s-triazolo / "4,3-a7- £" Λ , ^ ytenzodiazepine,

(2) 9-Bro] n-4,6-diethyl-1-trifluoromethyl-4H ~ s-triazolo- / ~ 4t3-a7ZT "i »IJtenzodiazepine,

(3) 1,9-Di (^ If luorraethyl) -6- (4-pyridyl) -4H-s-triaaolo-

(4) 8,1o-diethoxy ~ 9-diniethylaraino-4 ~ niethyl-6-0-pyridyl) -

1-trifluorinethyl-4H-s-triazolo / ~ 4 »3-a7 / ~ 1 _r £ 7benzodiazepine,

(5) 8-ethoxy-6 "(2-pyrryl) -1-trifluoromethyl-4H-s-triazolo-

(6) 9-Propylthio-1o-nitro-6-C 2-pyrimidyl) 1-trifluoromethyl

4H-s-triazolo / "4f3-a7 / ~ 1, ^ / kenzodiazepine,

(7) 8-chloro-4-ethyl-9-fluoro-6- (2-furyl) -1o-propylthio-1-

trifluoromethyl-4H-s-triazolo _J T "4,3-a7 /" i, £ 7 ^ enzodiazepine,

(8) 9-Ethyl-6- (3-furyl) -1o-methoxy-1-trifluoromethy1-4H-s-

(9) 8-chloro-1o-diethylamino-6- (2-pyrryl) -1-trifluoromethyl-4H-3 · triazolo / ~ 413-7 / ~ 1 _t £ 7t> en2odiazepiii,

(10) 1,9-di (trifluoromethyl) -1o-nitro-6- (2-thienyl) -4Η-ε-

(11) 8-Bromo-6- (1-propenyl) -4-propy1-1-trifluoromethy1-4H-striazolo / ~ 4.3 ~ a7 / ~ 1.47 "benzodiazepine _t

(12) 6-Isopropenyl-8-methoxy-9-nitro-1-trifluoromethyl-4H-ßtriazolo / ~ 4 ₁ 3-a7 ^ * 1,4.7 ^ enzodiazepine,

(13) 8-chloro ~ 9-ethoxy-1-trifluorraethyl-ö-vinyl ^ H-s-triazolo-

(14) 6-.Cyclopentyl-8-dipropylamino-i-trifluoromethy1-4H-S-

(15) G-Cycloheptyl-S-methoxy ^ -propyl-i-trifluoromethyl 1-4H-8-triazolo / "" 4,3-a7 / ~ * 1 , j ^^ enzodiazepine,

(16) 8-chloro-6- (1-cyclopentenyl) -9-ethoxy-1-trifluoromethyl 4H-s-triazolo / ~ 4f3-a

309817/1249

(17) 6- (i-Gycloheptenyl) -4,9-dim.eth.yl-8-methylthio-.1- Rifluoromethyl-4H-s-triazolo / ~ 4> 3-a7 / "i, 47benzodiazepine and the like

The 1- $ rifluorinethylverbindungen II obtained in this way can be converted into their acid addition salts according to the above procedure.

309812/1249

Claims (3)

Patent claims: 1 / compound of the general formula CP II wherein R _{1 is} a hydrogen atom or an alkyl radical with 1 to 3 carbon atoms, R2 is a pyridyl, 2-pyrimidyl, puryl, pyrryl or thienyl radical, a lower alkyl radical with 1 to 3 carbon atoms, a lower alkenyl radical with 2 to 3 carbon atoms, a cycloalkyl group with 5 to 7 carbon atoms or a cycloalkenyl group with 5 to 7 carbon atoms, R, and Rjj a hydrogen or halogen atom, a nitro, trifluoromethyl or a lower alkoxy group with 1 to 3 carbon atoms, a lower alkyl mercapto group with 1 to 3 carbon atoms or mean a lower dialkylamino radical with lower alkyl radicals having 1 to 3 carbon atoms, and their pharmaceutically acceptable acid addition salts. 2. 8-Bromo-6- (2-pyridyl) -l-trifluoromethyl-MH-s-triazolo [ll ^ -aj-flj ^ benzodiazepine as a compound according to claim 1, wherein R ₁ and R ^ are a hydrogen atom, R 1 Bromine atom and R2 denote a 2-pyridyl radical. 309812/1249 3. Process for the preparation of a compound of the general formula II wherein R _{1 is} a hydrogen atom or a lower alkyl radical with 1 to 3 carbon atoms, R _{2 is} a pyridyl, 2-pyrimidyl, puryl, pyrryl or thienyl radical, a lower alkyl radical with 1 to 3 carbon atoms, a lower alkenyl radical with 2 to 3 Carbon atoms, a cycloalkyl radical with 5 to 7 carbon atoms or a cycloalkenyl radical with 5 to 7 carbon atoms, R- * and R ^ a hydrogen or halogen atom, a nitro, trifluoromethyl or lower alkoxy radical with 1 to 3 carbon atoms, a lower one. Alkyl mercapto radical with 1 to 3 carbon atoms or a lower dialkylamino - 309812/1249 22U571 group consisting of alkyl radicals with 1 to 3 carbon atoms, and .depen pharrr.äkolögiach. compatible acid sai-i characterized »that one triiluoresaigßäure in the Cold with a compound of the formula NH-NH; in which R ₁ , Rp, R ^ and R. have the above meaning, mixed and the reaction mixture. heated to form compound II. For: ^- The Upjohn Company Kalamazoo, Mich., V.St.A, 309812/1249 (Dr. W. Beil) Lawyer BATH ORIGINAL